Blocking DNA Repair in Advanced BRCA-Mutated Cancer

Name of the Trial

Principal Investigator

Dr. Shivaani Kummar, NCI Center for Cancer Research

Why This Trial Is Important

Inherited mutations in the BRCA1 and BRCA2 genes can dramatically increase a woman's risk of breast and/or ovarian cancer. Mutated BRCA genes also increase the risk of a number of other cancers in both women and men.

The BRCA genes produce proteins that help repair DNA damage, specifically the repair of simultaneous breaks in both strands of DNA (called double-strand breaks). Cells with BRCA mutations are still viable, but, because they have a reduced ability to repair DNA damage, they accumulate mutations in additional genes, which can lead to the development and progression of cancer. Another family of genes called the PARP genes (PARP1 and PARP2) produces proteins that help repair single-strand breaks in DNA. Scientists have proposed that blocking the ability of PARP proteins to correct single-strand breaks in the DNA of cancer cells that have BRCA mutations will lead to cell death. The rationale for this proposal is that, by disrupting both types of DNA repair, the cells will be unable to survive. Consequently, a new class of experimental drugs that block the function of PARP proteins has been developed.

Several PARP inhibitors have been tested in laboratory studies and in clinical trials, but none has yet been approved for routine use in patients. One PARP inhibitor under development is called BMN 673. Preliminary studies of this drug suggested that it is more potent in blocking the action of PARP proteins than other drugs in this class, and early results of clinical trials show that the drug has activity against BRCA-mutated cancers.

In this trial, cancer patients with confirmed BRCA mutations who have not been treated previously with a PARP inhibitor will be given BMN 673 by mouth once a day in 28-day cycles. Treatment will continue until patients experience unacceptable side effects or their disease progresses. The patients will undergo a tumor biopsy before treatment begins and then again after treatment on the eighth day of the first cycle. Doctors want to see how the drug affects the tumor tissue (pharmacodynamic effect), as well as determine the response rates in patients with BRCA mutations who have breast cancer, ovarian or peritoneal cancer, or other solid tumors.

"This drug has demonstrated promising activity as a single agent in patients with refractory breast and ovarian cancers carrying BRCA mutations," Dr. Kummar said. "It is the most potent inhibitor of the PARP1 and PARP2 proteins currently in development. Our trial is designed to further evaluate the antitumor activity of this agent in breast and ovarian cancer, as well as in other solid tumors, and try to understand the effects of the drug in tumor cells. This would help us design future trials with this agent given in combination to further improve patient outcome," she explained.